The Q cell migrations in C elegans provide a wonderful opportunity to investigate fundamental aspects of cell patterning and positioning. The QL and QR neuroblasts are bilateral homologs that migrate in opposite directions. QR and its descendants migrate anteriorly, whereas QL and its descendants migrate posteriorly. During its migration, QL switches on the Hox gene mab-5, which, in turn, causes QL's descendants to migrate posteriorly instead of anteriorly. Ultimately, each Q-cell descendant migrates to a unique anteroposterior (A/P) position that does not correspond to any obvious landmarks. Thus, by studying Q cell migration, we can ask how left-right asymmetry is generated, how Hox gene regulation and function are integrated into a biological process, how guidance information can direct these complex migrations, and how guidance cues polarize the cytoskeleton and control cell movement. During this past funding period, we have found that these migrations are regulated by many interesting signaling proteins, both novel and conserved. These include Wnt pathway members, a netrin receptor, novel transmembrane proteins required for cell positioning and for left-right asymmetry, and a Rho family member, exchange factor, and integrin receptors required for migration itself. Many of the conserved signaling molecules behave in unexpected ways, making them especially interesting to investigate. During this funding period, we will identify missing components of this system by exploiting a rapid new screening procedure. In addition, by manipulating expression of genes we have characterized, we will ask how Q migration is regulated. For example, we will ask whether particular proteins specify left-right asymmetry, and whether extracellular guidance cues have permissive or instructive roles. In addition, we will investigate the functions of proteins that appear to polarize and move the Q cells by using GFP fusions to visualize intracellular events. Together these studies should help to define the molecular mechanisms that regulate and execute these migrations.